Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus.
Antipsychotics, old and new varieties, are effective against positive symptoms such as hallucination and delusions, but are often of limited value in treating core features of schizophrenia particularly negative symptoms. Developments of new drugs based on current dogmas have produced similar drugs with no breakthroughs in effectiveness. New knowledge as to which mechanisms are responsible for symptom productions and treatment is needed. There is evidence that response may improve when antipsychotics are augmented with selective serotonin reuptake inhibitor (SSRI). This augmenting effect cannot be explained by summating pharmacological effects of the individual drugs. In a series of laboratory and clinical studies, we identified unique biochemical effects of the SSRI-Antipsychotic combination, different from each individual drug and suggested that some of these may mediate the clinical effect. In this paper, we review these studies and propose that modulation of the gamma-aminobutyric acid (GABA)-A receptor and its regulating system is the mechanism by which SSRI antipsychotic synergism exerts its clinical efficacy.
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